PROJECT SUMMARY/ABSTRACT The Cancer Biology and Metastasis Program (CBMP) consists of 47 members (42 primary, 1 associate, 4 adjunct) from 20 departments. The program is led by Drs. Mien-Chie Hung, an international leader in cancer cell signaling, Menashe Bar-Eli, an expert in the biology of the tumor microenvironment, and Dihua Yu, whose laboratory studies mechanisms of cancer initiation, progression, metastasis, and therapeutic resistance. The program uses molecular and cellular biological approaches to understand the biology underlying the three themes of cancer cell signaling, tumor microenvironment, and metastasis, with the common goal of identifying therapeutic targets. Three specific aims are proposed. Aim 1: To improve our understanding of cancer cell signaling in tumor development, metastasis, and therapeutic resistance. Program members explore signaling pathways of growth factor receptors; inflammation and metabolism in cancer cells; and roles of epigenetic events such as post-translational modifications (PTM) and histone modifications, miRNAs, and ncRNAs in cancer growth. Aim 2: To delineate critical factors in the tumor microenvironment that drive tumor progression. Program members focus on how microenvironment-derived signals promote metastatic progression and facilitate epithelial-mesenchymal transitions (EMT)/cancer stem cells, angiogenesis and fibrosis. Aim 3: To investigate underlying mechanisms of metastasis and develop novel therapies to prevent or treat metastasis. Program members use animal models to study metastasis, examine the genetics and genomics of metastasis, and identify new oncogenic drivers that could serve as potential targets to prevent or treat metastatic disease. The annual direct peer-reviewed funding totals $9.6M with $5.3M (55%) from NCI grants. Since the last submission, the program has published 810 papers: 199 (25%) represent intra-programmatic collaborations, 436 (54%) represent inter-programmatic collaborations, and 602 (74%) represent inter-institutional collaborations. Sixty-nine percent of publications have appeared in journals with IF >5 and 29% in journals with IF >10, including Nature, Cell, Nat Med, Cancer Cell, Cancer Discov, Nat and Cell Biol. Program members utilize all 14 Shared Resources. During the last funding period, the program has a) identified a novel receptor tyrosine kinase-mediated signaling pathway regulating miRNA maturation (Shen J et al, Nature, 2013); b) demonstrated that EMT is dispensable for metastasis but induces chemoresistance in pancreatic cancer (Zheng X et al, Nature, 2015); c) provided a direct link of epigenetics to cancer metabolism (Wang Y et al, Nature, 2017); d) identified co-evolution between metastatic cancer cells and their microenvironment (Zhang L et al, Nature, 2015); e) demonstrated the oncogenic role of long non-coding RNAs in breast cancer metastasis (Xing Z et al, Cell, 2014); f) discovered a novel PTEN pathway and provided a means to track targetable vulnerabilities in cancers (Zhao D et al, Nature, 2017); and g) engineered exosomes to facilitate therapeutic targeting of oncogenic Kras (Kamerkar S et al, Nature, 2017).